Our objective is to understand the defect in cellular immunity that lead to autoimmune insulin-dependent diabetes mellitus (IDDM) using the BB rat disease model. Our hypothesis, developed over the last decade, is that IDDM in the BB rt results from an imbalance between beta cytotoxic effector cells and regulatory T cells. This hypothesis has been strengthened by two fundamental observations. First, we discovered that in BB rats the balance between auto-reactive and regulatory cells is already disequilibrated intrathymically. Large numbers of diabetogenic cells are present in the thymus of BB rats but not of normal animals. Second, we have obtained experimental evidence for the presence of multiple regulatory systems based on RT6+ regulatory cells. Second, we have obtained experimental evidence from the presence of multiple regulatory systems based on RT6+ regulatory cells, RT6 enzymatic activity, and soluble RT6 protein. Second Aim No. 1 is to investigate the antigen-specificity and activities of intrathymic autoreactive cells in BB rats. This aim will examine effects of intrathymic exposure to islet autoantigens, and the mechanism(s) involved in islet beta-cell-specific destruction by autoreactive cells. Specific Aim No. 2 is to investigate the mechanism(s) by which peripheral RT6+ regulatory cells, or RT6 protein itself, can modulate autoimmunity. The results of our studies will define the T cell populations in B rats that determine whether or not IDDM will occur. They will tell us how these populations interact and how the equilibrium between them is maintained or disrupted. We hope that an understanding of these cellular interactions will eventually translate into the design of rational strategies for the prevention of human juvenile diabetes.